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Multiple Mechanisms of Unfolded Protein Response-Induced Cell Death The American Journal of Pathology, Vol. 185, No. 7, July 2015 ajp.amjpathol.org ASIP COTRAN EARLY CAREER INVESTIGATOR AWARD LECTURE Multiple Mechanisms of Unfolded Protein ResponseeInduced Cell Death Nobuhiko Hiramatsu, Wei-Chieh Chiang, Timothy D. Kurt, Christina J. Sigurdson, and Jonathan H. Lin From the Department of Pathology, University of California-San Diego, La Jolla, California Accepted for publication March 26, 2015. Eukaryotic cells fold and assemble membrane and secreted proteins in the endoplasmic reticulum (ER), before delivery to other cellular compartments or the extracellular environment. Correctly folded pro- Address correspondence to Jonathan H. Lin, Department of teins are released from the ER, and poorly folded proteins are retained until they achieve stable Pathology, University of conformations; irreparably misfolded proteins are targeted for degradation. Diverse pathological in- California-San Diego, 9500 sults, such as amino acid mutations, hypoxia, or infection, can overwhelm ER protein quality control, Gilman Dr, La Jolla, CA leading to misfolded protein buildup, causing ER stress. To cope with ER stress, eukaryotic cells activate 92093-0612. E-mail: jlin@ the unfolded protein response (UPR) by increasing levels of ER protein-folding enzymes and chaper- ucsd.edu. ones, enhancing the degradation of misfolded proteins, and reducing protein translation. In mammalian cells, three ER transmembrane proteins, inositol-requiring enzyme-1 (IRE1; official name ERN1), PKR-like ER kinase (PERK; official name EIF2AK3), and activating transcription factor-6, control the UPR. The UPR signaling triggers a set of prodeath programs when the cells fail to successfully adapt to ER stress or restore homeostasis. ER stress and UPR signaling are implicated in the pathogenesis of diverse diseases, including neurodegeneration, cancer, diabetes, and inflammation. This review dis- cusses the current understanding in both adaptive and apoptotic responses as well as the molecular mechanisms instigating apoptosis via IRE1 and PERK signaling. We also examine how IRE1 and PERK signaling may be differentially used during neurodegeneration arising in retinitis pigmentosa and prion infection. (Am J Pathol 2015, 185: 1800e1808; http://dx.doi.org/10.1016/j.ajpath.2015.03.009) The endoplasmic reticulum (ER) is an essential organelle domains.1 In response to ER stress, IRE1 undergoes oligomeric responsible for folding of secreted and membrane proteins assembly, transautophosphorylation by its kinase domain, and and lipid and sterol biosynthesis, and it is a major site of activation of its distal RNase activity.2,3 In metazoans, the free calcium storage within the cell. Cells have evolved a RNase activity of activated IRE1 and the RtcB tRNA ligase unique homeostatic mechanism, termed the unfolded pro- splice out a small intron from the X-box binding protein-1 tein response (UPR), to ensure that the ER can adapt to (Xbp1) mRNA to produce XBP1s transcription factor.4e8 changing environmental and physiological demands of its functions. In mammalian cells, the UPR is controlled by Supported by NIH grants R01EY020846, R01NS069566, R01NS076896, and R01NS088485 and VA grant BX002284. the ER resident transmembrane proteins, inositol-requiring Disclosures: None declared. enzyme-1 (IRE1; official name ERN1), PKR-like ER The American Society for Investigative Pathology Cotran Early Career kinase (PERK; official name EIF2AK3), and activating Investigator Award recognizes early career investigators with demonstrated transcription factor-6 (ATF6). excellence as an investigator with recently established or emerging indepen- IRE1 is a transmembrane protein that controls a UPR signal dence and with a research focus leading to an improved understanding of the conceptual basis of disease. Jonathan H. Lin, recipient of the ASIP 2013 Cotran transduction pathway conserved from yeast to mammals 1 Early Career Investigator Award, delivered a lecture entitled Endoplasmic Re- (Figure 1). IRE1 bears a luminal domain coupled across the ER ticulum Stress in Disease Pathogenesis on April 22, 2013, at the annual meeting membrane to cytosolic kinase and endoribonuclease (RNase) of the American Society for Investigative Pathology in Boston, MA. Copyright ª 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajpath.2015.03.009 UPR in Disease Pathogenesis Normal Stress Unfolded Proteins BiP IRE1 PERK ATF6 SH S SH S P P b b P P K K Z P K P Z i K K i p R P P P P p R P P P eIF2α eIF2α S1P S2P XBP1s 40S bZip 60S XBP1s bZip Figure 1 Endoplasmic reticulum (ER) stress activates inositol-requiring enzyme 1 (IRE1), PKR-like ER kinase (PERK), and activating transcription factor-6 (ATF6) intracellular signal transduction pathways of the unfolded protein response (UPR). In normal condition, the UPR transducers, IRE1, PERK, and ATF6, associate with BiP to prevent UPR. On accumulation of misfolded proteins in the ER lumen, BiP dissociates to activate UPR transducers. IRE1 bears a luminal domain coupled across the ER membrane to cytosolic kinase (K) and endoribonuclease (RNase) domains (R). In response to ER stress, IRE1 undergoes oligomeric assembly, transautophosphorylation by its kinase domain, activating its distal RNase activity. Activated IRE1 splices out small intron from the X-box binding protein-1 (Xbp1) mRNA to generate active transcription factor XBP1s. The PERK protein bears luminal domain coupled across the ER membrane to K. In response to ER stress, PERK dimerizes and subsequently activates its cytosolic kinase domain. PERK’s kinase recognizes and phosphorylates eukaryotic translation initiation factor 2 subunit alpha (eIF2a), leading to attenuation of global protein translation. ATF6 bears an ER-tethered transcription factor. In response to ER stress, ATF6 migrates from the ER to the Golgi apparatus, where site 1 and 2 proteases (S1P and S2P, respectively) cleave its luminal and transmembrane domains, and release the cytosolic portion of ATF6 containing the bZIP transcriptional activator domain. Cleaved ATF6 fragment translocates to the nucleus to serve as a transcription factor. The transcriptional targets of XBP1 are highly enriched portion of ATF6 contains the bZIP transcriptional activator for ER-associated protein degradation (ERAD) factors, ER domain, and after cleavage, this ATF6 fragment migrates to chaperones, and enzymes required for lipid biosynthesis the nucleus to transcriptionally up-regulate ER chaperones and protein glycosylation across diverse mammalian cell and ERAD components, thereby enhancing ER protein- types.9e14 Up-regulation of these molecules by IRE1-to- folding capacity and efficiency of ERAD.10,12,18,20 Inter- XBP1s induction therefore enhances the ER’s capacity to estingly, ATF6 also transcriptionally up-regulates Xbp1, better fold new proteins as well as target irreparably thereby facilitating IRE1 signal transduction by increasing damaged proteins for retrotranslocation out of the ER for levels of IRE1’s RNase substrate, Xbp1 mRNA.21 degradation by proteasomes in the cytosol (Figure 1). Put together, these initial transcriptional and translational The ER transmembrane protein PERK regulates another effects of IRE1, PERK, and ATF6 signaling help cells adapt UPR signaling pathway in metazoans15 (Figure 1). On ER to ER stress by enhancing the fidelity of protein folding, stress, PERK oligomerizes and activates its cytosolic kinase increasing the degradation of damaged/misfolded proteins, domain.15 PERK’s kinase phosphorylates eukaryotic trans- and suppressing new protein synthesis. However, if these lation initiation factor 2 subunit alpha (eIF2a)onSer51, actions fail to restore ER homeostasis and ER stress persists, inhibiting the guanine nucleotide exchange factor eIF2B, which UPR signaling consequently triggers maladaptive proapo- converts inactive GDP-bound eIF2 to its active GTP form.15,16 ptotic programs, many of which are specifically activated Active eIF2 complex is needed to form the GTP-tRNAMet through the IRE1 and PERK pathways. ternary complex required for translation initiation. Therefore, eIF2a phosphorylation leads to translation inhibition that helps alleviate ER stress by reducing the load of new polypeptides IRE1 Signaling through RIDD, c-Jun N-Terminal that require assembly and folding in the ER compartment.17 Kinase, and BCL2 ATF6 bears an ER-tethered bZip transcription factor that regulates a third UPR signal transduction pathway18 Seminal mechanistic studies from the laboratory of Walter (Figure 1). In response to ER stress, ATF6 migrates from and colleagues have revealed that IRE1 undergoes dynamic the ER to the Golgi apparatus, where site 1 protease and site conformational and functional changes as a function of the 2 protease cleave its luminal and transmembrane domains to duration of ER stress. In response to acute ER stress, IRE1 release the cytosolic portion of ATF6.18,19 The cytosolic quickly forms oligomeric clusters in the ER plane, but IRE1 The American Journal of Pathology - ajp.amjpathol.org 1801 Hiramatsu et al Normal Acute Phase Chronic Phase P P P ? ? P K P K P P K K P P P P P R R R R TRAF2 ASK1 XBP1s RIDS RIDD P DR5 JNK BiP Cyp1a2 & Cyp2e1 ERAD Ces1 & Angptl3 Chaperone IRE1α Lipid Biosynthesis miRNAs Glycosylation Figure 2 Consequences of acute and chronic inositol-requiring enzyme 1 (IRE1) activation. In response to acute endoplasmic reticulum (ER) stress, IRE1 undergoes oligomeric assembly, undergoes transautophosphorylation by its
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